Myosin‐IIA regulates leukemia engraftment and brain infiltration in a mouse model of acute lymphoblastic leukemia

[摘要] Leukemiadissemination(thespreadofleukemiacellsfromthebonemarrow)andrelapseareassociatedwithpoorprognosis.Often,relapseoccursinperipheralorgans,suchastheCNS,whichactsasasanctuarysiteforleukemiacellstoescapeanti‐cancertreatments.Similartonormalleukocytemigration,leukemiadisseminationentailsmigrationofcellsfromthebloodcirculationintotissuesbyextravasation.Toextravasate,leukemiacellscrossthroughvascularendothelialwallsviaaprocesscalledtransendothelialmigration,whichrequirescytoskeletalremodeling.However,thespecificmolecularplayersinleukemiaextravasationarenotfullyknown.Weexaminedtheroleofmyosin‐IIAacytoskeletalclassIImyosinmotorprotein,inleukemiaprogressionanddisseminationintotheCNSbyuseofamousemodelofBcr‐Abl‐drivenBcellacutelymphoblasticleukemia.SmallhairpinRNA‐mediateddepletionofmyosin‐IIAdidnotaffectapoptosisorthegrowthrateofBcellacutelymphoblasticleukemiacells.However,inaninvivoleukemiatransfermodel,myosin‐IIAdepletionslowedleukemiaprogressionandprolongedsurvival,inpart,byreducingtheabilityofBcellacutelymphoblasticleukemiacellstoengraftefficiently.Finally,myosin‐IIAinhibition,eitherbysmallhairpinRNAdepletionorchemicalinhibitionbyblebbistatin,drasticallyreducedCNSinfiltrationofleukemiacells.Theeffectsonleukemiacellentryintotissuesweremostlyaresultoftherequirementformyosin‐IIAtoenableleukemiacellstocompletethetransendothelialmigrationprocessduringextravasation.Overall,ourdataimplicatemyosin‐IIAasakeymediatorofleukemiacellmigration,makingitapromisingtargettoinhibitleukemiadisseminationinvivoandpotentiallyreduceleukemiarelapses...

[学科分类] 生理学

[关键词] cytoskeleton;migration;extravasation;dissemination;Bcr‐Abl